This invention relates to a novel process for the production of polymeric powders having an average particle size of less than about 40 micrometers.
Enteric coating polymers are commonly used for tablets and particle coatings in preparing an oral dosage form. Polymers which are commonly used for enteric coating preparation include cellulosic materials such as cellulose acetate phthalate (C-A-P), cellulose acetate trimellate (C-A-T), cellulose acetate succinate (C-A-S), hydroxypropyl methylcellulose phthalate (HPMCP), hydroxypropyl methylcellulose acetate succinate (HPMCAS), copolymers of methacrylic acid and methyl methacrylate or ethyl acrylate, terpolymers of methacrylic acid, methacrylate, and ethyl acrylate, and polyvinyl acetate phthalate (PVAP). Among these polymers, cellulosic polymers are particularly prone to be hydrolyzed in contact with moisture, especially at elevated temperature.
In patent application WO99/20098, it is disclosed that for anti-viral and anti-bacterial purposes, the polymeric material, particularly C-A-P and HPMCP must be in the form of finely dispersed micronized particles of less than approximately 40 micrometers average particle size, dispersed in a water-miscible, non-solvent for the polymer, such as glycerol. In the WO99/20098 application, there was used a product containing from 63-70% micronized C-A-P, and from 30-33% other additives including poloxamer, distilled acetylated monoglycerides, and polysorbate 60. It is well known that poloxamer can cause the C-A-P to become unstable when subjected to heat and high moisture environments.
U.S. Pat. Nos. 4,177,177 and 4,330,338 describe an emulsification process for converting a water-insoluble polymeric material into a latex-like dispersion. It is known as pseudolatex process. In both patents, a combination of surfactant and emulsion stabilizer must be used in order to form a stable latex-like dispersion.
U.S. Pat. Nos. 4,960,814 and 5,025,004 by Wu et al. describe water-dispersible polymeric compositions and a process for preparing the compositions. The process makes stable colloidal latex-like dispersions of enteric coating polymers such as C-A-P and HPMCP, which can be spray dried in air to form water-dispersible powder materials. The process employs a combination of a water-in-oil and an oil-in-water emulsifier.
In the above-mentioned patents, the disclosed compositions comprise a polymer and a combination of at least two surface active materials in order to make stable latex emulsions or water-dispersible powders. The process uses both water-soluble and water-insoluble volatile organic solvents as vehicles in the preparation of an oil-in-water emulsion containing polymers, and then the organic solvent(s) is removed to yield a latex-like dispersion. The need for removing organic solvents in the process is very costly and undesirable. The dispersion is then spray-dried to form a water-dispersible powder product.
Therefore, it would be desirable to have a polymeric powder of less than about 40 micrometers average particle size, produced in the absence of necessarily introducing undesirable surfactants or other additives.
The novel process according to the present invention for the production of polymeric powders having an average particle size of about less than 40 micrometers, is comprised as follows. A solution of a suitable polymer that is soluble in polyethylene glycol, glycofurol, or propylene carbonate, is prepared, and the resulting solution is introduced into an aqueous medium which is under agitation such that there is produced a discrete droplet of polymer/solvent in aqueous medium. The solvent is removed and the polymer powder having an average particle size of less than about 40 micrometers is recovered. Preferably, the polymer powders have an average particle size of from about less than 1 to about 20 micrometers.
Polymer powders having an average particle size of less than about 40 micrometers, are useful in many applications such as antiviral, antimicrobial, for enteric coatings, for making tablets by direct compression, for granulating with medicaments to form particles, for adhesion in connection with topically applied medicaments, and the like.
The novel process according to the present invention for producing the polymer powder having an average particle size of less than about 40 micrometers, comprises:
(a) forming a solution of polymer in polyethylene glycol, or glycolfurol or propylene carbonate, or mixtures thereof, and
(b) introducing the resultant polymer-containing solution into an aqueous medium that is being agitated sufficiently such that there is produced a dispersion of discrete droplets of the polymer in the aqueous medium, the polymer having an average particle size of less than about 40 micrometers. As noted above, the polymer powder preferably has an average particle size of from about less than 1 to about 20 micrometers.
The polymer powder having an average particle size of less than about 40 micrometers can be recovered in any conventional manner. The following is the method(s) by which recovery of the polymer powder was achieved in the present application, starting with the dispersion of discrete polymer particles having an average particle size of less than about 40 micrometers, as obtained in step (b) above.
(c) the resulting dispersion of step (b) is allowed to stand without agitation until two distinct separate layers are formed, a white, cloudy upper layer, and a clear aqueous layer at the bottom.
(d) the two layers are separated by any means known in the art, such as, for example, by means of a separatory funnel, decantation, or the like, and the white cloudy upper layer containing the polymer is treated, as by centrifugation at approximately 1750 rpm (revolutions per minute), to remove aqueous solution from the dispersed particles, as a result of which treatment, as much as possible of unreacted polyethylene glycol or glycofurol or propylene carbonate, or mixtures thereof, and water, are removed,
(e) the resulting settled solid polymer is then washed with water and centrifuged, preferably three times, to remove excess polyethylene glycol, glycofurol or propylene carbonate, and to thereby yield a polymeric material,
(f) the polymeric material can be dried to remove water and thereby yield a fluffy polymer powder.
In an alternative embodiment, the polymeric material of step (e) can be mixed with an organic liquid that will prevent the particles from agglomerating. Any organic liquid may be used for this purpose, including, for example, glycerol, silicone oil, any oil, and the like. The resultant product, that may have a cream-like texture, may be used for many applications in this form.
The polymer(s) suitable for use in the present invention is any polymer(s), or mixtures thereof, that is water-insoluble, and is soluble in a solvent selected from polyethylene glycol having a weight average molecular weight of from about 200 to about 600, preferably from about 200 to about 450, or glycofurol, or propylene carbonate, or mixtures of the solvents. Exemplary of the suitable polymers are cellulose acetate phthalate (C-A-P), hydroxypropyl methylcellulose phthalate (HPMCP), cellulose acetate trimellitate (C-A-T), cellulose acetate succinate (C-A-S), hydroxypropyl methylcellulose acetate succinate (HPMCAS), cellulose acetate, cellulose butyrate, ethyl cellulose, polyvinyl acetate phthalate (PVAP), carboxymethylcellulose, carboxyvinyl polymer, and the like. Preferred for use are cellulose acetate phthalate (C-A-P) and hydroxypropyl methylcellulose phthalate (HPMCP).
The solvents in which the polymers of the present invention must be soluble are polyethylene glycol having a weight average molecular weight of from about 200 to about 600, preferably from about 200 to about 450, or glycofurol or propylene carbonate. The preferred solvent for use herein is polyethylene glycol having a weight average molecular weight of from about 200 to about 600.
In preparing the solution of polymer in the solvent selected from the polyethylene glycol having a weight average molecular weight of about 200 to about 600, or glycofurol or propylene carbonate, it is preferred that the solution comprise from about 5 to about 15%, preferably from about 5 to about 10% (percent) of polymer by weight. It is further desirable that the polymer-containing solution have a viscosity of about 500 to about 5000 cp at a selected temperature below the boiling temperature of water, that is below 100xc2x0 C.
The polyethylene glycol, glycofurol or propylene carbonate solvents herein may be used individually or in any combination or mixture thereof. Furthermore, the previously described solvent may be used optionally and preferably with water or a volatile organic solvent that is miscible with the polyethylene glycol, or glycofurol or propylene carbonate, or mixtures of water and solvent, as a solvent for the polymer. Exemplary of volatile organic solvents that are miscible with the polyethylene glycol, glycofurol or propylene carbonate, are acetone, ethanol, n-propanol, isopropanol, ethyl acetate, methyl ethyl ketone, methylene chloride, and the like. When utilized in this manner, the solvent selected from polyethylene glycol having a weight average molecular weight of about 200 to about 600, glycofurol or propylene glycol is present in a ratio to that of the water, volatile organic solvent, or mixture thereof, of from about greater than 3.2:1, preferably from about greater than about 4:1. Preferred for use herein with the solvent is water, acetone, or a mixture thereof.
The invention will be more readily understood by reference to the following examples. There are, of course, many other forms of this invention which will become obvious to one skilled in the art, once the invention has been fully disclosed, and it will accordingly be recognized that these examples are given for the purpose of illustration only, and are not to be construed as limiting the scope of this invention in any way.